17-67342182-T-C
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_002816.5(PSMD12):c.1161+4A>G variant causes a splice donor region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00006 in 1,551,272 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000059 ( 0 hom. )
Consequence
PSMD12
NM_002816.5 splice_donor_region, intron
NM_002816.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9876
2
Clinical Significance
Conservation
PhyloP100: 7.63
Genes affected
PSMD12 (HGNC:9557): (proteasome 26S subunit, non-ATPase 12) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator. A pseudogene has been identified on chromosome 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
BS2
High AC in GnomAd4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PSMD12 | NM_002816.5 | c.1161+4A>G | splice_donor_region_variant, intron_variant | ENST00000356126.8 | |||
PSMD12 | NM_001316341.2 | c.984+4A>G | splice_donor_region_variant, intron_variant | ||||
PSMD12 | NM_174871.4 | c.1101+4A>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PSMD12 | ENST00000356126.8 | c.1161+4A>G | splice_donor_region_variant, intron_variant | 1 | NM_002816.5 | P1 | |||
PSMD12 | ENST00000584008.5 | c.*1316+4A>G | splice_donor_region_variant, intron_variant, NMD_transcript_variant | 1 | |||||
PSMD12 | ENST00000357146.4 | c.1101+4A>G | splice_donor_region_variant, intron_variant | 2 | |||||
PSMD12 | ENST00000577724.1 | n.299+4A>G | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152226Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000323 AC: 8AN: 247532Hom.: 0 AF XY: 0.0000374 AC XY: 5AN XY: 133710
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GnomAD4 exome AF: 0.0000593 AC: 83AN: 1399046Hom.: 0 Cov.: 28 AF XY: 0.0000615 AC XY: 43AN XY: 698766
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GnomAD4 genome AF: 0.0000657 AC: 10AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74370
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 13, 2021 | The c.1161+4A>G intronic alteration consists of a A to G substitution 4 nucleotides after exon 10 of the PSMD12 gene. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at